CN114763334A - 一种左乙拉西坦3-位异构体杂质及其制备方法 - Google Patents
一种左乙拉西坦3-位异构体杂质及其制备方法 Download PDFInfo
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 34
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract description 34
- 239000012535 impurity Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000003908 quality control method Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OTVXVVYHNZUDSN-UHFFFAOYSA-N 3-aminobutanamide Chemical compound CC(N)CC(N)=O OTVXVVYHNZUDSN-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- NXTDJHZGHOFSQG-UHFFFAOYSA-N 3-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC(OC=2C=CC=CC=2)=C1 NXTDJHZGHOFSQG-UHFFFAOYSA-N 0.000 abstract description 10
- 238000001514 detection method Methods 0.000 abstract description 6
- 239000013558 reference substance Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 208000003078 Generalized Epilepsy Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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Abstract
本发明公开了一种左乙拉西坦3‑位异构体杂质(3‑(2‑吡咯烷酮‑1‑基)丁酰胺，简称3‑PBA)及其制备方法。本发明得到高纯度的左乙拉西坦3‑位异构体杂质(3‑PBA)，为左乙拉西坦产品的质量控制研究提供了可靠的杂质对照品和检测方法，具有十分重要的意义。
Description
技术领域
本发明涉及药物化学领域，具体涉及左乙拉西坦3-位异构体杂质及其制备方法。
发明背景
左乙拉西坦(英文名Levetiracetam)，化学名为(S)-2-(2-吡咯烷酮-1-基)丁酰胺，其结构式如下：
左乙拉西坦是比利时UCB公司开发的一种高效的、毒副作用小的广谱抗癫痫药，主要用于治疗局限性及继发性全身癫痫。
左乙拉西坦的最大日剂量为3000mg/天，根据ICH相关指导原则的规定，对于超过每日主成分最大日剂量为2g/天的产品，杂质的界定限为0.05％。超越界定限的杂质含量已经达到足以对人造成危害的数量。高于该限度的杂质应进行动物毒理研究，确定临床使用的安全限，且药品中的杂质含量应在效期内不大于该限度。
发明内容
在左乙拉西坦生产过程中，发明人发现某些异常批次有未知杂质水平较高，因此鉴定并且合成该杂质，建立该杂质的分析方法，对左乙拉西坦原料药的质量控制有重要意义。
本发明的一方面，是提供了一种新的3-位异构体杂质(简称3-PBA)，结构如下所示：
本发明的另一方面提供了一种操作简便，成本低廉的3-(2-吡咯烷酮-1-基)丁酰胺的合成方法。该方法以化合物3-氨基丁酰胺为起始原料，在碱性条件下与4-氯丁酰氯在溶剂中发生环合反应，制得左乙拉西坦3-位异构体杂质。
作为本发明的优选方案：
所述的溶剂为乙腈、二氯甲烷、N，N-二甲基甲酰胺、甲苯或水；溶剂用量与3-氨基丁酰胺的质量比为5.0:1～30:1，优选为8:1～15:1。
4-氯丁酰氯用量与3-氨基丁酰胺的摩尔比为1:1～3:1，优选为1.2:1～1.7:1。
反应可以在有催化剂或无催化剂存在下进行，优选在有催化剂存在时进行，所述的催化剂选自碘化钠、碘化钾、四丁基溴化铵、四乙基碘化铵、四丁基氯化铵；催化剂用量与3-氨基丁酰胺的摩尔比为0:1～0.5:1，优选为0:1～0.2:1。
所述的碱为氢氧化钠、氢氧化钾、碳酸钾或碳酸钠；碱用量与3-氨基丁酰胺的摩尔比为2.5:1～15:1，优选为3:1～6:1。
优选反应温度为0～120℃。
本发明新发现的3-PBA杂质与左乙拉西坦结构近似，较难精制去除，本发明通过确定该杂质的结构，以及提供定向合成该杂质的方法并得到高纯度的左乙拉西坦3-位异构体杂质(3-PBA)，为左乙拉西坦产品的质量控制研究提供了可靠的杂质对照品和检测方法，具有十分重要的意义。
附图说明
图1：左乙拉西坦3-位异构体(3-PBA)杂质检测图谱。
图2：左乙拉西坦样品检测图谱。
具体实施方式
下面结合实施例对本发明做进一步阐述，但是这些实例不对本发明构成任何限制。
实施例1：
左乙拉西坦3-位异构体杂质(3-PBA)的合成：
向500mL的三口瓶中，依次加入100g的乙腈，10.2g(0.1mol)的3-氨基丁酰胺，24g(0.6mol)的粉末氢氧化钠，搅拌，降温至0℃，缓慢滴加21.1g(0.15mol)的4-氯丁酰氯，滴完升温至30℃，搅拌反应15h。过滤，蒸干滤液，残留物柱层析纯化，即可得左乙拉西坦3-位异构体杂质，白色固体14.2g，HPLC纯度：97％，收率83％。1H NMR(CDCl3)δ＝1.19(d,3H),1.95-1.99(m,2H),2.32-2.42(m,3H),2.53-2.55(m,1H),3.33-3.37(m,2H),4.39-4.46(m,1H),5.73(br,1H),6.61(br,1H)；13C NMR(CDCl3)δ＝18.0,18.1,31.5,40.7,43.2,44.9,172.7,175.4.MS-ESI(m/z):[M+H]+171.2.
实施例2：
左乙拉西坦3-位异构体杂质(3-PBA)的合成：
向500mL的三口瓶中，依次加入100g的二氯甲烷，10.2g(0.1mol)的3-氨基丁酰胺，3.2g(0.01mol)的四丁基溴化铵，28g(0.5mol)的粉末氢氧化钾，搅拌，降温至0℃，缓慢滴加21.1g(0.15mol)的4-氯丁酰氯，滴完保持0～20℃，搅拌反应5h。过滤，蒸干滤液，残留物柱层析纯化，即可得左乙拉西坦3-位异构体杂质，白色固体14.4g，HPLC纯度：98％，收率85％。1H NMR(CDCl3)δ＝1.19(d,3H),1.95-1.99(m,2H),2.32-2.42(m,3H),2.53-2.55(m,1H),3.33-3.37(m,2H),4.39-4.46(m,1H),5.73(br,1H),6.61(br,1H)；13C NMR(CDCl3)δ＝18.0,18.1,31.5,40.7,43.2,44.9,172.7,175.4.MS-ESI(m/z):[M+H]+171.2.
实施例3：
左乙拉西坦3-位异构体杂质(3-PBA)的合成：
向500mL的三口瓶中，依次加入150g的二氯甲烷，10.2g(0.1mol)的3-氨基丁酰胺，5.1g(0.02mol)的四乙基碘化铵，45g(0.4mol)的50％氢氧化钾水溶液，搅拌，降温至0℃，缓慢滴加21.1g(0.15mol)的4-氯丁酰氯，滴完保持0～20℃，搅拌反应5h。过滤，蒸干滤液，残留物柱层析纯化，即可得左乙拉西坦3-位异构体杂质，白色固体12.9g，HPLC纯度：98％，收率76％。1H NMR(CDCl3)δ＝1.19(d,3H),1.95-1.99(m,2H),2.32-2.42(m,3H),2.53-2.55(m,1H),3.33-3.37(m,2H),4.39-4.46(m,1H),5.73(br,1H),6.61(br,1H)；13C NMR(CDCl3)δ＝18.0,18.1,31.5,40.7,43.2,44.9,172.7,175.4.MS-ESI(m/z):[M+H]+171.2.
实施例4：
左乙拉西坦3-位异构体杂质(3-PBA)和左乙拉西坦样品的检测：
检测条件：
进样浓度：左乙拉西坦3-位异构体杂质0.5μg/mL和左乙拉西坦样品10μg/mL分别进样
色谱柱：Inertsil ODS-3 150×4.6mm,5μm
缓冲盐：2.7g磷酸二氢钾溶于1000mL水中，用磷酸调节pH至4.5。
流动相A：缓冲盐：乙腈＝19:1(％V/V)
流动相B：乙腈
波长：205nm 柱温：30℃ 流速：0.9mL/min
进样量：10μL 运行时间：40min
梯度表：
| 时间(min) | 流动相A(％V/V) | 流动相B(％V/V) |
| 0 | 100 | 0 |
| 10 | 100 | 0 |
| 20 | 71 | 29 |
| 25 | 71 | 29 |
| 28 | 100 | 0 |
| 40 | 100 | 0 |
左乙拉西坦3-位异构体和左乙拉西坦样品的检测结果分别见图1和图2。
Claims (11)
1.一种左乙拉西坦3-位异构体杂质，其结构如下所示：
2.一种制备如权利要求1所述的左乙拉西坦3-位异构体杂质的方法，该方法以化合物3-氨基丁酰胺为起始原料，在碱性条件下与4-氯丁酰氯在溶剂中发生环合反应制得，合成路线如下所示：
3.根据权利要求2所述的制备方法，4-氯丁酰氯用量与3-氨基丁酰胺的摩尔比为1:1～3:1，优选为1.2:1～1.7:1。
4.根据权利要求2所述的制备方法，其特征在于，所述的溶剂为乙腈、二氯甲烷、N，N-二甲基甲酰胺、甲苯或水。
5.根据权利要求2所述的制备方法，其特征在于，溶剂用量与3-氨基丁酰胺的质量比为5.0:1～30:1，优选为8:1～15:1。
6.根据权利要求2所述的制备方法，其特征在于，反应在有催化剂存在时进行，所述的催化剂选自碘化钠、碘化钾、四丁基溴化铵、四乙基碘化铵、四丁基氯化铵。
7.根据权利要求6所述的制备方法，催化剂用量与3-氨基丁酰胺的摩尔比为0:1～0.5:1，优选为0:1～0.2:1。
8.根据权利要求2所述的制备方法，其特征在于，所述的碱为氢氧化钠、氢氧化钾、碳酸钾或碳酸钠。
9.根据权利要求2所述的制备方法，碱用量与3-氨基丁酰胺的摩尔比为2.5:1～15:1，优选为3:1～6:1。
10.根据权利要求2的制备方法，反应温度为0～120℃。
11.权利要求1所述的左乙拉西坦3-位异构体杂质，作为左乙拉西坦产品质量控制研究的杂质对照品的用途。
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